The invention generally relates to polymer medical devices for insertion into a body.
Surgery or injury often leads to the problem of tissue adhesion. For example, injury, incision or abrasion of the peritoneum, pleural or abdominal cavity causes release of a serosanguinous exudate. The exudate coagulates, which leads to production of fibrinous bands between abutting surfaces. These bands can organize by fibroblast proliferation to become collagenous adhesions.
Adhesions can also form at sites of bone fractures. Bony spurs promote the formation of fibrous adhesions between the fracture site and neighboring tissue. Surgery caused adhesions are generally undesirable. For example, adhesions can impair normal movement between bones and tendons, cause bowel obstructions and disrupt nerve transmissions.
Approaches to reduction of post-surgical adhesion include the application of drugs or surfactants, and use of collagen, collagen-fabric, collagen membranes or reconstituted collagen as physical barriers. Other barriers are made from polyester, collagen, amino acids polymers and chitin.
In situ methods of barrier formation have utilized carboxyl-containing polysaccharides. Barriers can consist of a polysaccharide solution, covalently cross-linked polysaccharide or ionically cross-linked polysaccharide.
Hyaluronic acid (xe2x80x9cHAxe2x80x9d) is a polysaccharide that has been used for anti-adhesion applications. To provide greater stability, HA can be cross-linked in a patient with a number of ionically cross-linking solutions, such a ferric chloride solution. Alginate is another polysaccharide that can be used for anti-adhesion purposes. The barrier is formed at a desired site by simultaneous spraying of polysaccharide solution and cross-linking solution, injection of solutions or spreading a foam or gel at the site.
The invention generally involves low cost, easy to place and reposition anti-adhesion barrier sheets. Prior methods and devices for reduction of trauma site adhesion have several deficiencies. In situ formation of barriers creates the need for use of more equipment and expenditure of more time and effort by a medical worker. In situ formation also leads to a barrier of variable properties. The exact degree of cross-linking, thickness of a material, and location of the material will vary from patient to patient. Prior methods of use of cross-linked polysaccharides prevent easy removal of barrier material from a patient. Though much used, HA is very expensive and provides barriers of limited physical stability and lifetime.
The invention also generally involves adhesion barriers that have low cost and are easy to use. Adhesion barriers according to the invention do not require in situ formation, have a lifetime in a body of up to two weeks or more, and permit a medical worker to both reposition and fix the barrier at a desired location. The invention generally relates to a repositionable, long life, low cost barrier sheet that a medical worker can suture to tissue. The invention also generally relates to a container-based drug delivery device.
In one aspect, the invention features a device for insertion into a body to reduce adhesion. The device comprises a sheet comprising ionically cross-linked alginate. The sheet has sufficient mechanical stability to allow suturing of the sheet to a body tissue. The sheet provides a barrier to reduce adhesion between the body tissue and a neighboring body tissue.
In one embodiment, the sheet has a thickness in a range of 0.25 mm to 10 mm. In a further embodiment, the sheet has a tear strength in a range of 5 psi to 500 psi. In a further embodiment, the sheet can be fabricated, or cut by a medical worker, in a variety of shapes, including a polygon, an oval and a disk. In another embodiment, more than 25 wt % of the sheet is water.
In one embodiment, an outer portion of the sheet has a lower density of cross-linking relative to an inner portion of the sheet. In a further embodiment, the device includes a suture for tying the sheet to a tissue.
In another aspect, the invention features a drug delivery device for insertion in a body. The device comprises a container that comprises mechanically stable ionically cross-linked alginate. In one embodiment, the container is filled with one or more drugs and inserted in a body.
In one aspect, the invention features a method of forming a sheet for use as an adhesion barrier. The method comprises forming a film from an alginate solution, and contacting the film with a cross-linking solution to form a cross-linked mechanically stable sheet. At least a portion of the sheet can be placed at a site of trauma to create the adhesion barrier. In one embodiment, the method includes suturing the portion of the sheet to secure it to the site of trauma.
In one embodiment, the method further comprises selecting a quantity of the alginate solution to yield a sheet having a thickness in a range of 0.25 mm to 10 mm. In another embodiment, contacting comprises waiting a preselected period of time to obtain a preselected density of cross-linking. In one embodiment, the alginate film is stored prior to contacting with the cross-linking solution.
In one embodiment, contacting is accomplished by pouring. In another embodiment, contacting is accomplished by spraying. In still another embodiment contacting is accomplished by extrusion of the film of alginate solution into a bath of cross-linking solution.
In one embodiment, the film from an alginate solution is formed by dipping a substrate into a bath of the alginate solution. In another embodiment, contacting is accomplished by dipping the substrate in a bath of the cross-linking solution.
In a further embodiment, the cross-linked mechanically stable sheet is contacted with an ion stripping agent to reduce a density of cross-linking in an outer portion of the sheet relative to an inner portion of the sheet.
In one embodiment of the invention, the alginate solution comprises water and a water soluble alginate selected from the group consisting of sodium alginate, potassium alginate, magnesium alginate or propylene glycol alginate.
In one embodiment, the cross-linking solution comprises a divalent or trivalent metal salt. The salt can be, for example, a salt of barium, calcium, copper, cobalt, aluminum, iron, boron, beryllium, lead or silver. In another embodiment, the alginate solution comprises alginic acid having an active ester or aldehyde at a carboxylate site, and the cross-linking solution comprises a bifunctional cross-linker.
In another embodiment, the alginate solution comprises a filler. The fillers can be radiopaque materials to allow visualization of the barrier within the body, both during and after placement at a desired target site. The fillers can be materials that increase the mechanical strength of the barrier, for example pieces of non-dissolvable polymer material, such as suture material, or other non-dissolvable materials. In another embodiment, the filler is a lifetime enhancer that comprises a sulfate of calcium, barium, strontium, copper, zinc or iron.
In another embodiment, the alginate solution includes one or more polymers selected from the group consisting of a biodegradable polymer, a polysaccharide, a polyester and a polymer with covalent cross-linking. The polymers are selected to modify the elastic modulus and hydrophobicity of the sheet.
In another embodiment, the alginate solution comprises an additive for medical treatment, for example, an antiseptic, an antibiotic, an anticoagulant, a contraceptive, a nucleic acid molecule, a protein, and a medicine. In another embodiment, the alginate solution comprises a biocompatible dye to assist observation of sheet location in a body. In other embodiments of the invention, a filler or other additive is included in the cross-linking solution.
In another aspect, the invention provides a method of making a drug delivery device for insertion in a body. The method comprises forming a film from an alginate solution, and contacting the film with a cross-linking solution to cross-link an outer portion of the film. An interior portion of the film remains substantially non-cross-linked and is drained through an opening in the outer portion. In one embodiment, the outer portion is then filled with one or more drugs and inserted in a body. In another embodiment, the method further comprises inserting cross-linking solution into the drained outer portion to further cross-link the outer portion.
The foregoing and other objects, aspects, features, and advantages of the invention will become more apparent from the following description and from the claims.